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  • 1. Use of 5 -Reductase Inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology/ American Urological Association 2008 Clinical Practice Guideline Barnett S. Kramer, Karen L. Hagerty, Stewart Justman, Mark R. Somerfield, Peter C. Albertsen,* William J. Blot, H. Ballentine Carter, Joseph P. Costantino, Jonathan I. Epstein, Paul A. Godley,† Russell P. Harris, Timothy J. Wilt, Janet Wittes,‡ Robin Zon and Paul Schellhammer§ From the National Institutes of Health, Bethesda, MD; American Society of Clinical Oncology, Alexandria, VA; University of Montana Liberal Studies, Missoula, MT; University of Connecticut Health Center, Farmington, CT; International Epidemiology Institute, Rockville, MD; Johns Hopkins University, Baltimore, MD; National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA; University of North Carolina at Chapel Hill, Chapel Hill, NC; University of Minnesota School of Medicine, Minneapolis, MN; Statistics Collaborative,Washington, DC; Michiana Hematology Oncology, Granger, IN; and Eastern Virginia Medical School, Norfolk, VA Approved by the American Society of Clinical Oncology Board on July 21, 2008, and by the Purpose: To develop an evidence-based guideline on the use of 5- -reductase American Urological Association Board on Octo- ber 17, 2008. inhibitors (5-ARIs) for prostate cancer chemoprevention. This document is being reprinted as sub- Methods: The American Society of Clinical Oncology (ASCO) Health Services mitted without editorial or independent peer Committee (HSC), ASCO Cancer Prevention Committee, and the American Uro- review by the Editors of The Journal of Urology®. logical Association Practice Guidelines Committee jointly convened a Panel of This guideline was developed through a col- experts, who used the results from a systematic review of the literature to develop laboration between the American Society of Clin- evidence-based recommendations on the use of 5-ARIs for prostate cancer che- ical Oncology and the American Urological Asso- ciation, and has been published jointly by moprevention. invitation and consent in the Journal of Clinical Results: The systematic review completed for this guideline identified 15 ran- Oncology and The Journal of Urology®. No part domized clinical trials that met the inclusion criteria, nine of which reported of this document may be reproduced or transmit- ted in any form or by any means, electronic or prostate cancer period prevalence. mechanical, including photocopy, recording or Conclusion: Asymptomatic men with a prostate-specific antigen (PSA) 3.0 any information storage and retrieval system, ng/mL who are regularly screened with PSA or are anticipating undergoing without written permission by the American So- ciety of Clinical Oncology or the American Uro- annual PSA screening for early detection of prostate cancer may benefit from a logical Association. discussion of both the benefits of 5-ARIs for 7 years for the prevention of prostate * Financial interest and/or other relationship cancer and the potential risks (including the possibility of high-grade prostate with GlaxoSmithKline. † Financial interest and/or other relationship cancer). Men who are taking 5-ARIs for benign conditions such as lower urinary with GlaxoSmithKline. tract [obstructive] symptoms (LUTS) may benefit from a similar discussion, ‡ Financial interest and/or other relationship understanding that the improvement of LUTS relief should be weighed with the with Merck. § Financial interest and/or other relationship potential risks of high-grade prostate cancer from 5-ARIs (although the majority with Theralogix, Dendreon Corporation, South- of the Panel members judged the latter risk to be unlikely). A reduction of western Oncology Group and ContraVac. approximately 50% in PSA by 12 months is expected in men taking a 5-ARI; See Editorial on page 000. however, because these changes in PSA may vary across men, and within indi- vidual men over time, the Panel cannot recommend a specific cut point to trigger a biopsy for men taking a 5-ARI. No specific cut point or change in PSA has been prospectively validated in men taking a 5-ARI. INTRODUCTION prevention interventions applicable Surveys1,2 of American Society of to clinical practice, and most respon- Clinical Oncology (ASCO) members dents envision increased utilization of have shown strong interest in cancer prevention in their practices. Chemo- 0022-5347/09/1814-1642/0 Vol. 181, 1642-1657, April 2009 THE JOURNAL OF UROLOGY® Printed in U.S.A. 1642 www.jurology.com Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2009.01.071
  • 2. 5 -REDUCTASE INHIBITORS GUIDELINE 1643 prevention, a strong area of research, is particularly harms and benefits of taking 5-ARIs for preventing relevant to practicing oncologists and urologists be- prostate cancer. As part of its deliberations, the cause its application is well suited to the clinical Panel also evaluated the outcomes of the PLESS setting in which shared decision making takes place (Proscar Long-Term Efficacy and Safety Study) and between health professionals and individual pa- MTOPS (Medical Therapy of Prostatic Symptoms) tients. To date, the strongest evidence of efficacy in trials, which examined 5-ARIs for the relief of uri- the field of chemoprevention has come from the hor- nary tract obstruction, because reduced incidence of monally responsive tumors: breast cancer with ta- urinary tract obstruction is one of the potential ben- moxifen and raloxifene3,4 and prostate cancer with efits of 5-ARI use. The charge to the Panel was to the 5- -reductase inhibitor (5-ARI).5 Unlike most judge the balance of benefits and harms. other chemopreventive agents under study, such as cyclooxygenase-2 inhibitors and retinoids, tamox- ifen and finasteride have been shown definitively in GUIDELINE QUESTIONS randomized clinical trials to decrease the incidence This guideline addresses the use of 5-ARIs in pre- of invasive cancers—not just surrogate end venting prostate cancer. The overarching question points—in healthy people.3– 6 Nevertheless, these was should men routinely be offered a 5-ARI for the agents have adverse effects that require careful dis- chemoprevention of prostate cancer? To address this cussion with patients considering whether or not to question, the committee identified important compo- take the agent. nents likely to influence assessments of the balance Although substantial data are available on the of risks and benefits and decision making that re- use of 5-ARIs in other settings—primarily, treat- quired evaluation: ment of benign prostatic hyperplasia (BPH)7–10— the Prostate Cancer Prevention Trial (PCPT) is the 1. What is the impact of 5-ARIs on the risk of inci- only completed randomized trial prospectively de- dent prostate cancer, prostate cancer mortality, signed to show a reduction in period-prevalence of and overall mortality? Do benefits and harms of prostate cancer.5 The PCPT investigators reported a 5-ARIs vary among identifiable subpopulations decrease in cumulative incidence of prostate cancer (eg, age, race/ethnicity, family history, baseline from 24.4% in the placebo arm to 18.4% in the fin- risk for prostate cancer) and by type of 5-ARI? asteride arm during the 7 years of the trial. Never- 2. Do 5-ARIs have a differential effect on the devel- theless, an observed increase of Gleason scores 7 to opment of different histologic grades or stages of 10 in the finasteride study arm (37%, or 280 of 757 prostate cancer? Are any such differences likely tumors) compared with the placebo arm (22.2%, or to modify the curability of prostate cancer when 237 of 1,068 tumors), noted in a secondary analysis, diagnosed? Is the Gleason histologic grading sys- triggered concern about harm. tem for prostate cancer applicable to men who are These issues complicate informed decision mak- receiving 5-ARIs or other interventions that tar- ing by patients who are considering finasteride for get the androgen pathway? prostate cancer chemoprevention, and are impor- 3. What is the impact of 5-ARIs on the need for tant to the many men taking finasteride for the treatment of benign prostatic disease? management of BPH or for male pattern baldness. 4. What is the impact of 5-ARIs on quality of life? Published proposals discuss the balance of risks and What are other potential harms and adverse ef- benefits of finasteride for the prevention of prostate fects of 5-ARIs? What are other potential benefits cancer,11 although some have questioned the as- of, and indications for, 5-ARI use (eg, benign pros- sumptions used in the calculation as overly favor- tatic hyperplasia, male baldness)? able.12 Because of the importance of the issue to both 5. How long should treatment continue for the best clinical oncologists and urologists, ASCO has collab- outcome (period v lifelong)? orated with the American Urological Association 6. What are the future directions of research re- (AUA) to develop a clinical practice guideline on the garding 5-ARIs for the prevention of prostate benefits and harms of 5-ARIs for the prevention of cancer? prostate cancer. New information will likely become available from ongoing analyses in the PCPT and the results of the REDUCE (Reduction by Dutas- PRACTICE GUIDELINES teride of Prostate Cancer Events) trial,13 a preven- Practice guidelines are systematically developed tion trial testing dutasteride, which inhibits both statements to assist practitioners and patients in isoforms (types 1 and 2) of 5- -reductase. This guide- making decisions about appropriate health care for line, sponsored by ASCO and AUA, aims to provide specific clinical circumstances. Attributes of good a useful tool for clinicians and their patients in guidelines include validity, reliability, reproducibil- making an informed decision about the potential ity, clinical applicability, clinical flexibility, clarity,
  • 3. 1644 5 -REDUCTASE INHIBITORS GUIDELINE multidisciplinary process, review of evidence, and ultimate determination regarding its application to documentation. Guidelines may be useful in produc- be made by the physician in light of each patient’s ing better care and decreasing cost. Specifically, uti- individual circumstances. ASCO and AUA guide- lization of clinical guidelines may provide the follow- lines and assessments describe the use of procedures ing: and therapies in clinical practice and cannot be as- sumed to apply to the use of these interventions in 1. Improvement in outcomes the context of clinical trials. ASCO and AUA assume 2. Improvement in medical practice no responsibility for any injury or damage to persons 3. Means for minimizing inappropriate practice or property arising out of or related to any use of variation ASCO and AUA’s guidelines or assessments, or for 4. Decision support tools for practitioners any errors or omissions. 5. Points of reference for medical orientation and education 6. Criteria for self-evaluation METHODS 7. Indicators and criteria for external quality re- Panel Composition view The ASCO Health Services Committee (HSC) and the 8. Assistance with reimbursement and coverage AUA Practice Guidelines Committee jointly convened an decisions Expert Panel (hereafter referred to as the Panel) consist- 9. Criteria for use in credentialing decisions ing of experts in clinical medicine and research methods 10. Identification of areas where further research is relevant to chemoprevention for prostate cancer. The ex- needed. perts’ fields included medical oncology, urology, pathology, epidemiology, statistics, and health services research. The In formulating recommendations for the use of Panel included academic and community practitioners as 5-ARIs for prostate cancer prevention, ASCO and well as a patient representative. The Panel members are AUA have considered these tenets of guideline de- listed in Appendix Table A1. velopment, emphasizing review of data from appro- Literature Review and Analysis priately conducted and analyzed clinical trials. Wilt et al systematic review. The AUA commissioned a These same tenets can be utilized and applied to systematic review of the literature on the role of 5-ARIs in formulation of prevention guidelines. However, it is the chemoprevention of prostate cancer. That review, important to note that guidelines cannot always ac- which is published in the Cochrane Library,14 served as count for individual variation among patients. the primary source of evidence for this guideline. Articles Guidelines are not intended to supplant physician were selected for inclusion in the systematic review if they judgment with respect to particular patients or spe- met the following prospective criteria: (1) a randomized cial clinical situations and cannot be considered in- controlled trial (RCT) that examined a 5-ARI versus a clusive of all proper methods of care or exclusive of control; (2) treatment period that was at least 1 year; (3) study population that consisted of men age 45 years or other treatments reasonably directed at obtaining older; (4) period prevalence of prostate cancer was one of the same result. the reported outcomes; and (5) the study was published ASCO and AUA’s practice guidelines and technol- after 1984. For nonprostate cancer outcomes, randomized ogy assessments reflect expert consensus based on trials were selected for inclusion if they met the following clinical evidence and literature available at the time criteria: (1) treatment period was at least 6 months; (2) an they are written, and are intended to assist physi- RCT compared a 5-ARI to a nonactive control or to another cians in clinical decision making and identify ques- active treatment; (3) study population consisted of men tions and settings for further research. Due to the age 45 years or older; (4) at least one of the secondary rapid flow of scientific information in oncology, new outcomes of interest chosen by the Panel were reported; and (5) the study was published after 1999. This date was evidence may have emerged since the time a guide- chosen because the AUA guideline on the management of line or assessment was submitted for publication. BPH included studies published through 1999.7 PCPT Guidelines and assessments are not continually up- authors provided unpublished information at the request dated and may not reflect the most recent evidence. of the panel. Additional details of the literature search Guidelines and assessments cannot account for in- strategy and meta-analyses are provided elsewhere.14 dividual variation among patients, and cannot be ASCO/AUA Expert Panel literature review and analy- considered inclusive of all proper methods of care or sis. The Panel reviewed all data from the primary studies exclusive of other treatments. It is the responsibility contained in the systematic review; subsequently, the of the treating physician or other health care pro- Panel considered the results of the meta-analyses con- vider, relying on independent experience and knowl- tained in the systematic review. edge of the patient, to determine the best course of Consensus Development Based on Evidence treatment for the patient. Accordingly, adherence to A steering committee met in October 2005. The steering any guideline or assessment is voluntary, with the committee was charged with identifying potential Panel
  • 4. 5 -REDUCTASE INHIBITORS GUIDELINE 1645 members and with drafting the clinical questions the ered to represent mild symptoms; 8 to 19, moderate; and Panel was to address. In August 2006 the entire Panel 20 to 35, severe. A change in score by 2 to 3 points is met; the Panel completed its additional work through generally accepted as clinically meaningful (ie, morbid teleconferences. The purposes of the Panel meeting were and/or life threatening). to refine the questions addressed by the guideline and to make writing assignments for the respective sections. All Summary of Outcomes Assessed members of the Panel participated in the preparation of The primary outcome assessed was either prostate cancer the draft guideline, which was then disseminated for re- incidence or period prevalence, in prostate cancers de- view by the entire Panel. Feedback from external review- tected “for cause.” For-cause cancers were defined as those ers was also solicited. The ASCO HSC and the AUA Prac- that (1) were suspected clinically during the course of the tice Guidelines Committee, as well as the Board of trial because of symptoms, abnormal digital rectal exam, Directors of both organizations, reviewed and approved or abnormal PSA (ie, a PSA that exceeded a certain value the content of the guideline and the manuscript before or rate of increase over time) and were confirmed on bi- dissemination. opsy; or (2) during the trial, a recommendation was made for biopsy according to the study protocol (eg, due to in- Guideline and Conflicts of Interest creasing PSA) which was never done, and end-of-study All members of the Expert Panel complied with the ASCO biopsy showed prostate cancer; or (3) end-of-study biopsy and AUA policies on conflicts of interest, which require in the setting of a PSA more than 4 or a suspicious digital disclosure of any financial or other interest that might be rectal examination (DRE) showed prostate cancer. construed as constituting an actual, potential, or apparent Other primary outcomes assessed were distribution of conflict. Members of the Expert Panel completed disclo- stage of prostate cancer, Gleason scores, and incidence or sure forms and were asked to identify ties to companies period prevalence of prostate cancer by age, race, baseline developing products that promulgation of the guideline PSA, and family history. might affect. Information was requested regarding em- Secondary outcomes included prostate cancer detected ployment, consultancies, stock ownership, honoraria, re- purely for reasons dictated by study protocol, rather than search funding, expert testimony, and membership on by clinical indication (eg, an end-of-study biopsy was re- company advisory committees. The Panel made decisions quired per protocol despite a PSA 4 ng/mL, and DRE not on a case-by-case basis as to whether an individual’s role suggestive of cancer), and overall incidence or period prev- should be limited as a result of a conflict. No limiting alence of prostate cancer (ie, cancers detected for cause conflict was identified. plus cancers detected by study protocol). Other secondary outcomes included quality of life; change in validated uri- Revision Dates nary symptom scale scores (IPSS/AUA); BPH progression At biannual intervals, the Panel Co-Chairs and two Panel (development of acute urinary retention, interventions for members designated by the Co-Chairs will examine cur- treatment of LUTS, medications and herbal therapies to rent literature to determine if there is a need for revisions treat LUTS, surgical interventions); overall mortality; to the guideline. If necessary, the entire Panel will recon- prostate cancer-specific mortality; adverse events (impo- vene to discuss potential changes. When appropriate, the tence, retrograde ejaculation, decreased ejaculate volume, Panel will recommend revision of the guideline to the decreased libido, gynecomastia); and cost effectiveness. ASCO HSC, the ASCO Board, the AUA Practice Guide- Neither formal cost effectiveness nor decision analysis lines Committee, and the AUA Board for review and ap- was planned for the guideline, although the Panel consid- proval. ered available reports. Definition of Terms Period prevalence: the proportion of the randomized pop- RESULTS ulation identified as having prostate cancer over the trial period. Literature Search 5- -reductase: an enzyme that converts testosterone Wilt et al14 identified 15 RCTs that met the inclu- into the more potent dihydrotestosterone (DHT). 5- -Re- sion criteria; nine of these trials reported prostate ductase has two isoenzymes (isoforms): types 1 and 2. cancer period-prevalence. Finasteride inhibits the type 2 isoenzyme, whereas dutas- teride inhibits both the type 1 and type 2 isoenzymes. Previous Guidelines and Consensus Statements Primary prevention: Intervention for relatively healthy Updated in 2003,7 the 1999 AUA guideline on the individuals with no invasive cancer and an average risk management of benign prostate hyperplasia can be for developing cancer.15 summarized as follows: Chemoprevention: the use of chemical compounds to Finasteride, a 5-ARI, demonstrates both efficacy reduce the risk of development of a specific disease (as and acceptable safety for treatment of LUTS due to used here, specifically for the reduction in risk of develop- ing prostate cancer). BPH. Finasteride can reduce the size of the prostate, LUTS: Lower urinary tract [obstructive] symptoms. can increase peak urinary flow rate, and can reduce AUA Symptom Index/International Prostate Symptom BPH symptoms. With finasteride, the average pa- Score (IPSS): a symptom index for BPH, developed by the tient experiences a 3-point improvement in the AUA AUA. The IPSS consists of seven questions, with scores Symptom Index. In general, patients perceive this ranging from 0 to 35. A score between 0 and 7 is consid- level of symptom improvement as a meaningful
  • 5. 1646 5 -REDUCTASE INHIBITORS GUIDELINE change. Finasteride is ineffective for relief of lower Evidence Summary urinary tract obstructive symptoms in patients who The summary of evidence of the effect of 5-ARIs on do not have enlarged prostates. Reported adverse prostate cancer period prevalence is based on nine events are primarily sexually related; they include RCTs in which administration of the 5-ARI ranged decreased libido, ejaculatory dysfunction, and erec- from 1 to 7 years.14 Two additional trials lasting at tile dysfunction, which are reversible and therefore least 6 months provided data on BPH-related out- uncommon after the first year of therapy. Symptom comes and adverse effects. Most of the trials were score improvement is not substantially greater placebo controlled and double-blinded (Appendix among men with very large versus only moderately Table A2). The results of all trials were generally enlarged prostates; however, because of the more consistent. The most salient end point chosen by the progressive nature of the disease in men with larger Panel was the comparison in trials of at least 1 year glands or higher PSA values, such patients conser- duration of period prevalence of for-cause prostate vatively treated (watchful or placebo groups) face an cancers between study arms, as defined in the Meth- increasingly higher risk of complication, thereby en- ods section and glossary, using an intent-to-treat hancing the difference over time in outcomes be- analysis (five studies). This end point comes closest tween finasteride and no treatment or placebo to addressing prevention of those cancers that are groups. In summary, finasteride reduces the risk of sub- considered most important in clinical decision mak- sequent acute urinary retention and the need for ing—those diagnosed because of symptoms, DRE BPH-related surgery with the absolute benefit in- that is clinically suggestive, or a PSA that triggers a creasing with rising prostate volume or serum PSA. biopsy. Only one of the randomized trials, the pla- Finasteride is not appropriate treatment for men cebo-controlled PCPT, was specifically designed to with LUTS who do not have any prostatic enlarge- assess the period prevalence of prostate cancer in ment. generally healthy men without underlying moderate or severe lower urinary track symptoms. The PCPT was the largest trial in the literature, with 18,882 of RECOMMENDATIONS the total 33,403 participants in trials receiving at Should Men Routinely Be Offered a 5-ARI for least 1 year of active therapy. The PCPT also con- the Chemoprevention of Prostate Cancer? tributed approximately 85% (1,006 of 1,188) of the Asymptomatic men with a PSA 3.0 who are for-cause cancers in the systematic review.14 Men in regularly screened with PSA or are anticipating un- all of the trials were screened regularly for prostate dergoing annual PSA screening for early detection of cancer with PSA and DRE. Therefore, the literature prostate cancer may benefit from a discussion of the reviewed does not allow assessment of the impact of benefits of 5-ARIs for 7 years for the prevention of 5-ARIs on the period prevalence of prostate cancer prostate cancer and the potential risks (including among men who are not being actively screened for the possibility of high-grade prostate cancer) to be prostate cancer. able to make a better-informed decision. Men who are taking 5-ARIs for benign conditions such as Review of Relevant Literature LUTS would benefit from a similar discussion. What is the impact of 5-ARIs on the risk of incident Of note, one Panel member believed that the ex- prostate cancer, prostate cancer mortality, and over- planation of decreased prostate cancer period prev- all mortality? Do benefits and harms of 5-ARIs vary alence in the finasteride arm of the PCPT is attrib- among identifiable subpopulations (eg, age, race/eth- utable to differential biopsy rates between the two nicity, family history, baseline risk for prostate can- trial arms. The 25% risk reduction is based primar- cer) and by type of 5-ARI? ily on the PCPT and the risk reduction of a prostate diagnosis accrued primarily as a result of the lower 5-ARIs decrease the period prevalence of for- rates of biopsy among men on finasteride. For those cause prostate cancer by approximately 26% (rela- men who underwent a biopsy, the risk reduction was tive risk 0.74; 95% CI, 0.67 to 0.83; Fig 1). The a statistically nonsignificant 10%. By contrast, the absolute risk reduction is about 1.4% (4.9% in con- principal investigator of the PCPT has published a trols v 3.5% in 5-ARI arms), although this may vary commentary stating that differential biopsy rate is with the age of the treated population. (For compar- not likely to account for a substantial proportion of ison, the data from the Breast Cancer Prevention the observed difference. He argues that critics of the Trial3 suggest that about 100 women with a 2% PCPT “. . . ignore the effects of PSA, DRE, and bi- baseline risk of breast cancer would have to be opsy detecting the cancer in the finasteride group, treated for approximately 6 years with tamoxifen to which would be expected to further reduce the risk prevent one case of invasive breast cancer.) The of cancer overall.” relative risk of any prostate cancer with 5-ARI treat-
  • 6. 5 -REDUCTASE INHIBITORS GUIDELINE 1647 Review: 5-alpha reductase inhibitors (5-ARIs) and prostate cancer prevention Comparison: 5-ARI versus placebo Outcome: Prostate cancer detected “for cause” Study 5-ARI Placebo RR (fixed) or subcategory n/N n/N 95% CI RR (fixed) 95% CI 01 Finasteride: Mid-term duration (1 to 2 years) FSG American 1992 3/595 1/300 1.51 (0.16 to 14.48) FSG Int. 1993 5/495 3/255 0.86 (0.21 to 3.56) PROSPECT 1996 3/310 6/303 0.49 (0.12 to 1.94) Subtotal (95% CI) 1,400 858 0.74 (0.30 to 1.79) Total events: 11 (5-ARI), 10 (Placebo) Test for heterogeneity: χ2 = 0.78, df = 2, P = .68, I2 = 0% Test for overall effect: z = 0.67, P = .50 02 Finasteride: Long-term treatment duration (> 2 years) PCPT 2003 435/9,423 571/9,459 0.76 (0.68 to 0.86) PLESS 1998 36/1,524 45/1,516 0.80 (0.52 to 1.23) Subtotal (95% CI) 10,947 10,975 0.77 (0.68 to 0.86) Total events: 471 (5-ARI), 616 (Placebo) Test for heterogeneity: χ2 = 0.03, df = 1, P = .86, I2 = 0% Test for overall effect: z = 4.45, P < .00001 03 Dutasteride: Long-term treatment duration (> 2 years) ARIA/ARIB 2004 27/2,167 55/2,158 0.49 (0.31 to 0.77) Subtotal (95% CI) 2,167 2,158 0.49 (0.31 to 0.77) Total events: 27 (5-ARI), 55 (Placebo) Test for heterogeneity: not applicable Test for overall effect: z = 3.07, P = .002 Total (95% CI) 14,514 13,991 0.74 (0.67 to 0.83) Total events: 509 (5-ARI), 681 (Placebo) Test for heterogeneity: χ2 = 4.31, df = 5, P = .51, I2 = 0% Test for overall effect: z = 5.17, P < .00001 0.2 0.5 1 2 5 Favors 5-ARI Favors Placebo Figure 1. Prostate cancer detected for cause. 5-ARI, 5- -reductase inhibitor; RR, relative risk; FSG, Finasteride Study Group; PROSPECT, Proscar Safety Plus Efficacy Canadian Two-Year study; PCPT, Prostate Cancer Prevention Trial; PLESS, Proscar Long-Term Efficacy and Safety Study. Adapted with permission from the Cochrane Collaboration. ment versus controls was 0.74 (95% CI, 0.56 to 0.98), cise, especially with regard to race/ethnicity, be- for an absolute risk reduction of 2.9% (9.2% v 6.3%; cause approximately 92% of the participants in the Fig 2). PCPT were non-Hispanic whites. The PCPT is the most relevant of the trials con- Importantly, the participants in all the trials sidered because its target population was men with were being actively screened for prostate cancer. at most mild lower urinary track symptoms who had This study design issue affects the interpretation of a normal DRE and PSA less than 3 ng/mL at study the potential effect of 5-ARIs on the risk of develop- entry. This population is probably closest to a true ing prostate cancer. For example, regular screening primary prevention population. In the PCPT, the with PSA is known to double the incidence of diag- relative risk of for-cause prostate cancers among nosed prostate cancer.16 The relative reduction in those receiving finasteride versus placebo was 0.76 risk of being diagnosed with prostate cancer of ap- (95% CI, 0.68 to 0.86). This reduction corresponds to proximately 26% must be interpreted in this con- the need to treat approximately 71 healthy men for text, yielding a net increase in prostate cancer diag- approximately 7 years to prevent one case of pros- noses of approximately 48% for the combined tate cancer (95% CI, 50 to 100). strategy of screening plus chemoprevention. The Only the PCPT reported subgroup results by race/ studies provide no information as to whether the ethnicity, age, and family history of prostate cancer. magnitude of risk reduction for the diagnosis of The data showed no apparent difference in efficacy prostate cancer achieved by 5-ARIs would be the of finasteride within any of these subgroups (Appen- same, or considerably less, in men who are not being dix Table A3), but estimates are necessarily impre- actively screened for prostate cancer.
  • 7. 1648 5 -REDUCTASE INHIBITORS GUIDELINE Review: 5-alpha reductase inhibitors (5-ARIs) and prostate cancer prevention Comparison: 5-ARI versus placebo Outcome: Prostate cancer detected overall Study 5-ARI Placebo RR (random) or subcategory n/N n/N 95% CI RR (random) 95% CI 01 Finasteride: Mid-term treatment duration (1 to 2 years) Cote 1998 8/27 1/25 7.41 (1.00 to 55.09) FSG American 1992 3/595 1/300 1.51 (0.16 to 14.48) FSG Int. 1993 5/495 3/255 0.86 (0.21 to 3.56) PROSPECT 1996 3/310 6/303 0.49 (0.12 to 1.94) Subtotal (95% CI) 1,427 883 1.23 (0.40 to 3.78) Total events: 19 (5-ARI), 11 (Placebo) Test for heterogeneity: χ2 = 5.17, df = 3, P = .16, I2 = 42.0% Test for overall effect: z = 0.37, P = .71 02 Finasteride: Long-term treatment duration (> 2 years) PCPT 2003 803/9,423 1,147/9,459 0.70 (0.65 to 0.77) PLESS 1998 72/1,524 77/1,516 0.93 (0.68 to 1.27) Subtotal (95% CI) 10,947 10,975 0.78 (0.60 to 1.01) Total events: 875 (5-ARI), 1,224 (Placebo) Test for heterogeneity: χ2 = 2.86, df = 1, P = .09, I2 = 65.1% Test for overall effect: z = 1.91, P = .057 03 Dutasteride: Long-term treatment duration (> 2 years) ARIA/ARIB 2004 27/2,167 55/2,158 0.49 (0.31 to 0.77) Subtotal (95% CI) 2,167 2,158 0.49 (0.31 to 0.77) Total events: 27 (5-ARI), 55 (Placebo) Test for heterogeneity: not applicable Test for overall effect: z = 3.07, P = .002 Total (95% CI) 14,541 14,016 0.74 (0.56 to 0.98) Total events: 921 (5-ARI), 1,290 (Placebo) Test for heterogeneity: χ2 = 11.51, df = 6, P = .07, I2 = 48.0% Test for overall effect: z = 2.09, P = .036 0.1 0.2 0.5 1 2 5 10 Favors 5-ARI Favors Placebo Figure 2. Prostate cancer detected overall. 5-ARI, 5- -reductase inhibitor; RR, relative risk; FSG, Finasteride Study Group; PROSPECT, Proscar Safety Plus Efficacy Canadian Two-Year study; PCPT, Prostate Cancer Prevention Trial; PLESS, Proscar Long-Term Efficacy and Safety Study. Adapted with permission from the Cochrane Collaboration. None of the trials was large enough to detect modify the curability of prostate cancer when diag- clinically important differences in either prostate nosed? Is the Gleason histologic grading system for cancer-specific mortality or overall mortality, and no prostate cancer applicable to men who are receiving difference was noted. The summary relative risk of 5-ARIs or other interventions that target the andro- prostate cancer-specific mortality from the random- gen pathway? ized trials was 1.00, with wide 95% CIs (0.29 to The original publication and analysis of the PCPT 3.47). Likewise, the relative risk for all-cause mor- screening trial5 reported a statistically significant tality for 5-ARIs versus controls was 1.06 (95% CI, reduction in the 7-year period prevalence of prostate 0.95 to 1.18). Absolute rates of prostate cancer mor- cancer when finasteride was compared with placebo. tality and overall mortality were 0.5% and 5.0%, A secondary analysis showed an unexpected statis- respectively. Nevertheless, the Panel judged that tically significant greater number of high Gleason even if 5-ARI treatment never translates into re- grade cancers in the finasteride treatment arm. For duced overall or prostate cancer-specific mortality, every thousand men, finasteride reduced the num- reduction in risk of prostate cancer diagnosis with ber of prostate cancers from 60 to 45; however, if the the consequent morbidity of treatment is a clinically observations represent a true finding, the number of beneficial end point in and of itself. high-grade cancers would increase from 18 to 21 in Do 5-ARIs have a differential effect on the devel- this cohort.14 The concern of paramount importance opment of different histologic grades or stages of was the potential causal relationship of finasteride prostate cancer? Are any such differences likely to to high-grade cancer. The PCPT investigators, prac-
  • 8. 5 -REDUCTASE INHIBITORS GUIDELINE 1649 ticing physicians, and the Panel all struggled with ceiver operating characteristic curves demonstrate the question of whether the increase in high-grade heightened sensitivity of both PSA and DRE in the cancers reflected a real risk of finasteride or merely finasteride arm relative to the placebo arm, suggest- confounding factors. ing an enhanced suspicion for (and detection of) Several subsequent analyses of the data from the prostate cancer in the finasteride arm.20 It is reas- trial have addressed this question. An initial con- suring that despite the greater proportion of pa- cern centered about the morphologic and histopatho- tients with biopsy Gleason scores of 7 in the finas- logic alterations that might be attributed to a hor- teride group relative to placebo, patients from the monal agent or an agent, such as finasteride, which two groups who subsequently were treated with rad- alters the hormonal milieu. Might morphologic ical prostatectomy showed no difference in patho- changes caused by finasteride mimic high-grade logic stage, nodal involvement, or margin status. cancer, and therefore artifactually produce a higher This observation, however, was possibly driven by Gleason reading? A detailed pathologic review elim- differential choices in the decision to undergo radi- inated the questions of morphologic artifact as a cal prostatectomy. reason for the higher number of Gleason grade tu- In summary, the Panel judged that plausible rea- mors in the finasteride arm.17 sons could have led to a spurious increase in high- A second question that was addressed by the grade cancers. The Panel believed that it was un- PCPT investigators was the degree of sampling er- likely for an agent to increase the incidence of high- ror induced by the established effect of 5-ARIs on grade tumors and simultaneously decrease the reduction in prostate volume. Finasteride reduces incidence of low-grade tumors. Furthermore, at this prostate volume by approximately 25% to time there is no known pathologic adjustment factor 30%.5,9,10,18 The smaller the prostate volume, the for men diagnosed with prostate cancer while taking less likely the sampling error using the PCPT’s pro- a 5-ARI versus men not taking a 5-ARI. Nor is there tocol-prescribed systematic sextant needle biopsies. information on the long-term outcomes for a given Biopsies of the smaller prostates increase the likeli- histologic grade for men taking a 5-ARI versus men hood of detection of prostate cancer of all grades. If not having received a 5-ARI. Therefore, until this finasteride is more effective in preventing low-grade information is known, decisions regarding the nat- tumors than high-grade tumors, it is possible to ural history of the disease and decisions regarding observe a reduction in overall period prevalence of treatment interventions should be based on the his- cancers, a reduction in low- and moderate-grade tologic information obtained on biopsy, regardless of cancers, but an absolute increase in high-grade can- 5-ARI status. Such an effect would be difficult to cers as a consequence of less sampling error in the explain on the basis of known biologic mechanisms. finasteride arm. Indeed, modeling incorporating Nevertheless, none of the observations provides prostate volume suggests that the increase in high- proof that finasteride would not increase the true grade cancers seen in the PCPT may be nearly com- incidence of high-grade cancers. Therefore, men pletely explained by enhanced detection and not tu- should be fully apprised of the remaining uncer- mor transformation or induction, and would not be tainty surrounding high-grade cancers with finas- expected to translate into an increase in prostate teride. cancer mortality.18 Lastly, a detailed analysis of core biopsy speci- A series of multivariable logistic regression mod- mens compared standard prognostic findings for els was used to predict the incidence of high-grade cancers detected in the finasteride and placebo arms cancer in the finasteride and placebo arms.19 A and made the following observations. For cancers model that did not incorporate grading information assigned Gleason score 6, the mean number of from radical prostatectomies showed a nonsignifi- cores positive was 1.4 in the finasteride arm and cant 14% increase in high-grade cancer (P .12) in 1.55 in the placebo arm (P .024); the mean per- the finasteride group; however, incorporating infor- centage of cores positive for Gleason score 7 was 31.2 mation on grading led to a 27% lower (P .02) and 36.7 (P .009); and for cancers assigned Glea- bias-adjusted estimated rate of high-grade cancer in son score 8, bilateral core positivity was 28.6% in the finasteride arm (6.0%) than in the placebo arm the finasteride arm and 44.6% in the placebo arm (8.2%). Although subject to the uncertainty of mod- (P .047). These data suggest that men taking eling assumptions outcomes, this analysis lends ad- finasteride had smaller, less aggressive tumors ver- ditional support against high-grade disease induc- sus men taking placebo.21 tion by finasteride. Apart from chemoprevention for prostate cancer, A third question of potential bias revolves around many men take a 5-ARI for indications such as lower the possibility of differences between the finasteride urinary tract obstructive symptoms or male pattern and placebo study arms of the PCPT in the operating baldness. The observed increase in high-grade pros- characteristics of PSA and DRE. Analysis by re- tate cancers in men receiving finasteride in the
  • 9. 1650 5 -REDUCTASE INHIBITORS GUIDELINE PCPT, and the theoretical possibility of increased placebo, albeit of small absolute magnitude (Table risk of prostate cancer mortality, should be dis- 1). Virtually all RCTs show a 2% to 4% increase in cussed with these men. The considerations men- reported erectile dysfunction and gynecomastia, and tioned above provide some reassurance that the in- decreases in ejaculate volume and libido for the crease in diagnosis of high-grade tumors is more treatment arm. When all studies, mid- and long- likely to be due to artifact than to an actual increase term, were combined, the overall discontinuation or in aggressive cancers. In such cases, observed bene- loss to follow-up rates for both the 5-ARI and placebo fits must be weighed against theoretical harms in arms were approximately 15%. The combined dis- men who are being treated for symptomatic or both- continuation and loss to follow-up rate specifically ersome conditions. secondary to adverse events was approximately 6% What Is the Impact of 5-ARIs on the Need for to 7% in studies in both the 5-ARI and placebo Treatment for Benign Prostatic Disease? patients. When the PCPT specifically evaluated ad- 5-ARIs are established, US Food and Drug Ad- verse events, there were more adverse effects caus- ministration-approved, treatments for symptomatic ing temporary discontinuation in the finasteride arm BPH. The systematic review of trials in men with (the investigators do not specifically define tempo- established BPH confirmed the efficacy of this class rary in this setting). Sexual function and endocrine of drugs for this condition. To date, only the PCPT effects, which were more common in the 5-ARI arm provides information that directly addresses the im- (statistically significant), included decreased libido, pact of 5-ARIs in relatively asymptomatic men who decreased ejaculate volume, and gynecomastia. The do not require treatment of urinary tract symptoms. sexual dysfunction associated with finasteride de- In the PCPT, the incidence of acute urinary reten- creased over time, although it remained statistically tion was decreased by about one third in the finas- teride arm (RR 0.67; 95% CI, 0.59 to 0.76; absolute significant. The magnitude of effect was smaller rates, 6.3% v 4.2%). Consistent with this observa- than natural sources of variability in the study pop- tion, the incidence of transurethral resection of the ulation23; on a scale of 0 to 100 (a higher score prostate was 1.9% in the placebo arm and 1.0% in indicates more sexual dysfunction), the largest effect the finasteride arm, a statistically significant de- of finasteride on sexual functioning was a difference crease in the risk for surgical interventions. (mean) of 3.21 points, compared with a difference of What is the impact of 5-ARIs on quality of life? 1.26 points for each year of older age. What are other potential harms and adverse effects of In trials comparing 5-ARIs to an alpha blocker for 5-ARIs? What are other potential benefits of, and the management of LUTS, discontinuation rates indications for, 5-ARI use (eg, benign prostatic hy- were similar in the two groups. Dizziness and pos- perplasia, male baldness)? tural hypertension were statistically more frequent among patients receiving 5- blocker therapy.10,24,25 Benefits of 5-ARI. The question of the impact of 5-ARIs on global quality of life is difficult to answer 5-ARIs effect on PSA. The decrease in PSA levels by based on the available data. Studies of 5-ARIs have 5-ARIs must be taken into account when judging the not assessed global or general health-related quality significance of a PSA level. In the PCPT, finasteride of life using traditional quality-of-life measures; lowered the PSA by 50% after 12 months of therapy, rather, most studies have included measures of uri- and therefore a multiplier of 2 was used as a crite- nary symptoms (eg, urinary retention), sexual func- rion for biopsy. The effects of 5-ARIs on PSA before tioning (eg, erectile dysfunction), and/or endocrine 12 months are variable. In the PCPT, the decline at effects (eg, gynecomastia). Mid- and long-term stud- 3 years was greater than 50% which was adjusted by ies (6 months or beyond) with finasteride and dutas- changing the 2 multiplier in the finasteride arm to teride individually and in meta-analysis of studies 2.3. that included men with underlying LUTS demon- A single study has investigated the changes in strated a reduction in risk in acute urinary retention PSA level caused by a 1-mg dose, as is used in (from 5.6% to 3.3%; absolute risk difference, 2.3%) as treatment of male pattern baldness.26 For men age well as a reduction in the need for surgical interven- 50 years and older, 1 mg of finasteride had an effect tion (from 3.3% to 1.7%; absolute risk difference, similar to 5 mg (50% decrease) at the 1-year fol- 1.6%). The largest benefits were observed in men low-up date. Information beyond 1 year is not with a baseline PSA greater than 4 ng/mL (larger available. prostates). In addition, one RCT showed a statisti- Dutasteride inhibits both the type 1 and type 2 cally significant reduction in hematuria with finas- isoforms of 5- reductase and causes a greater and teride compared with placebo.22 more consistent decrease in DHT. The amount of Adverse events. 5-ARIs are associated with a con- PSA suppression with long-term dutasteride treat- sistently higher frequency of adverse events than ment has not been reported.
  • 10. 5 -REDUCTASE INHIBITORS GUIDELINE 1651 Table 1. Adverse effects 5- -Reductase Inhibitor Placebo Subgroup/Reference No./Total No. % No./Total No. % Relative Risk 95% CI Impotence/erectile dysfunction Mid-term treatment duration (1 to 2 years) ARIA/ARIB8 13/1,605 0.81 14/1,555 0.90 0.90 0.42 to 1.91 FSG-American47 25/595 4.2 5/300 1.7 2.52 0.97 to 6.52 FSG-International48 22/495 4.4 1/255 0.4 11.33 1.54 to 83.60 PREDICT24 13/264 4.9 9/269 3.3 1.47 0.64 to 3.38 PROSPECT41 49/310 15.8 19/303 6.2 2.52 1.52 to 4.18 VA COOP25 29/310 9.4 14/305 4.6 2.04 1.10 to 3.78 Long-term treatment duration ( 2 years) PCPT5 6,349/9,423 67.4 5,816/9,457 61.5 1.10 1.07 to 1.12 Total 6,500/13,002 50.0 5,878/12,444 47.2 1.71 1.11 to 2.65 Decreased/abnormal ejaculate volume Mid-term treatment duration (1 to 2 years) FSG-American47 26/595 4.4 5/300 1.7 2.62 1.02 to 6.76 VA COOP25 6/310 1.9 4/305 1.3 1.48 0.42 to 5.18 Long-term treatment duration ( 2 years) PCPT5 5,690/9,423 60.4 4,473/9,457 47.3 1.28 1.24 to 1.31 Finasteride Long-Term Efficacy and Safety Study Group36 23/1,524 1.5 8/1,516 0.53 2.86 1.28 to 6.37 Total 5,745/11,852 48.5 4,490/11,578 38.8 1.75 1.07 to 2.85 Decreased libido Mid-term treatment duration (1 to 2 years) ARIA/ARIB8 91/2,167 4.2 46/2,158 2.1 1.97 1.39 to 2.79 FSG-American47 32/595 5.4 4/300 1.3 4.03 1.44 to 11.30 PREDICT24 9/264 3.4 5/269 1.9 1.83 0.62 to 5.40 PROSPECT41 31/310 10.0 19/303 6.2 1.59 0.92 to 2.76 VA COOP25 14/310 4.5 4/305 1.3 3.44 1.15 to 10.34 Long-term treatment duration ( 2 years) PCPT5 6,163/9,423 65.4 5,635/9,457 59.6 1.10 1.07 to 1.22 Total 6,340/13,069 48.5 5,713/12,792 44.7 1.83 1.19 to 2.81 Gynecomastia Mid-term treatment duration (1 to 2 years) ARIA/ARIB8 50/2167 2.3 16/2158 0.74 3.11 1.78 to 5.45 Long-term treatment duration ( 2 years) PCPT5 426/9,423 4.5 261/9,457 2.8 1.64 1.41 to 1.91 Total 476/11,590 4.1 277/11,615 2.4 2.13 1.15 to 3.95 Incontinence Long-term treatment duration ( 2 years) MTOPS10 7/768 0.91 6/737 0.81 1.12 0.38 to 3.32 PCPT5 183/9,423 1.9 208/9,457 2.2 0.88 0.73 to 1.07 Total 190/10,191 1.9 214/10,194 2.1 0.89 0.73 to 1.08 Increased urinary frequency/urgency PCPT5 1,214/9,423 12.9 1,474/9,457 15.6 0.83 0.77 to 0.89 Abbreviations: FSG, Finasteride Study Group; PREDICT, Prospective European Doxazosin and Combination Therapy trial; PROSPECT, Proscar Safety Plus Efficacy Canadian Two-Year study; VA COOP, Veterans Affairs Cooperative Studies BPH Study Group; PCPT, Prostate Cancer Prevention Trial. MTOPS, Medical Therapy of Prostatic Symptoms. Adapted with permission from the Cochrane Collaboration. In conclusion, a consistently uniform scale multi- the efficacy of a 5-ARI (finasteride) for preventing plier is currently unavailable because of inter- and prostate cancer. It is also the most reliable trial intraindividual variability of PSA levels, laboratory for directly comparing the benefits and harms of variables, variable compliance of patients with re- finasteride in the most likely target population for gard to drug schedule, and a paucity of data relating interventions to prevent prostate cancer. Given change of PSA to duration of therapy. No specific cut that finasteride was administered for a planned 7 point or change in PSA has been prospectively vali- years, the Panel judged that until additional in- dated in men taking a 5-ARI. formation is available, finasteride should be given What is the treatment duration required for best for 7 years if used for primary prevention. One outcome (period versus lifelong)? ongoing trial13 compares dutasteride with placebo No trial has directly compared different durations for preventing prostate cancer. Dutasteride is ad- of 5-ARIs for the prevention of prostate cancer. The ministered for 4 years in that trial, so the results PCPT was the only reported trial designed to test of the trial should help address the question of
  • 11. 1652 5 -REDUCTASE INHIBITORS GUIDELINE whether a shorter duration of a 5-ARI prevents pecially earlier onset disease or as a second prostate cancer. malignancy. What are the future directions of research regard- ing 5-ARIs for the prevention of prostate cancer? The goal of developing a chemopreventive agent PHYSICIAN-PATIENT COMMUNICATION that can reduce the risk of prostate cancer has been Although the decision to embark on a preventive achieved. Nevertheless, despite the availability of 5-ARI regimen belongs in the final analysis to the one large and well-designed trial (PCPT) and an individual, the physician has an important role. For ongoing large trial (REDUCE) to test the efficacy of the man who is considering the use of these agents finasteride and dutasteride, respectively, for the pri- for prostate cancer prevention, it is essential that mary prevention of prostate cancer, important ques- the physician present the available data and high- tions and directions for research remain. The critical light the remaining uncertainty. question regarding the effect of 5-ARIs on prostate 5-ARIs do not eliminate the risk of developing cancer morbidity and mortality is yet to be an- prostate cancer; they reduce its clinical incidence. swered: is the observed increase in higher grade This distinction should be made clear. The advisabil- prostate cancers in men receiving finasteride in the ity of the drug as a chemopreventive agent depends PCPT real or artifactual? Additional investigation is on an estimate of probabilities— of risk. As yet, necessary, and the results of REDUCE will aid in there is no widely established decision model or aid this assessment. that can help a man of age 50 or 60 years determine The dose of finasteride currently being used to if he is well advised to take a 5-ARI. Thompson et treat male pattern baldness is 1 mg per day rather al27,28 have developed a prostate cancer risk calcu- than the 5 mg per day used in the PCPT. It is lator based on risk equations generated from the unknown if a 1-mg dose is as effective as 5 mg in PCPT data that may have clinical applications. The reducing the risk of prostate cancer. If the lower risk calculator is applicable to men who are similar dose is just as effective, the balance of benefits and to those who participated in the PCPT: at least 50 harms would be more favorable. All of this informa- years of age, no prior prostate cancer diagnosis, and tion would be critical to making more reliable esti- PSA and DRE results that are less than 1 year old. mates of cost effectiveness of 5-ARIs for preventing The calculator provides a preliminary assessment of prostate cancer. It would also be important to know prostate cancer risk and the risk of high-grade pros- whether 5-ARIs reduce the incidence of clinically tate cancer if a prostate biopsy is performed, and detected cancer among men who are not being ac- was recently validated in a more ethnically diverse tively screened. This would be especially pertinent and a younger population than that studied in the should the ongoing randomized trials of prostate PCPT.29 The calculator is accessible at http://www. cancer screening (Prostate, Lung, Colorectal, Ovary compass.fhcrc.org/edmnci/bin/calculator/main.asp? [PLCO] Screening Study; European Randomized t prostate&sub disclaimer&v prostate&m &x Study of Prostate Cancer [ERSPC]) show that pros- Prostate%20Cancer. tate cancer screening does not decrease prostate It is uncertain whether the findings of increased cancer mortality or that the harms of screening out- high-grade cancers on the finasteride arm of the weigh the benefits. In addition, as mentioned above, PCPT are actually an artifact of the methodology of men taking a 5-ARI are expected to experience a the PCPT itself, as many believe. Until that risk is roughly 50% reduction in PSA by 12 months; how- better elucidated, physicians should be explicit ever, because these changes in PSA may vary across about the uncertainties. In addition, it is important men, and within individual men over time, the to point out that the impact of 5-ARIs on prostate Panel cannot recommend a specific cut point to trig- cancer mortality is unknown, given that the PCPT ger a biopsy for men taking a 5-ARI. This is an was not designed to address this question. Never- important topic for future research. theless, it is clear that a 5-ARI does convey benefits Behavioral and communication research is to some men, as it decreases the overall incidence of needed on the type and effectiveness of information prostate cancer and also prevents urinary tract ob- for men considering the use of a 5-ARI for preven- struction in some men. tion of prostate cancer and for men who are already In communicating the present state of knowledge taking a 5-ARI for other indications. More generally, about the risks and benefits of 5-ARIs, it may be as models incorporating molecular data evolve, risk- helpful to use the model of a cohort of 1,000 men stratification models may be developed to tailor in- taking 5-ARIs for 7 years. Based on the systematic dividual preventive therapy. Such models may in- review by Wilt et al,14 it is estimated that 5-ARIs clude individuals with germline susceptibility at will result in a reduction of 15 prostate cancer cases heightened risk for developing prostate cancer, es- in this group of 1,000 men, and in a possible increase
  • 12. 5 -REDUCTASE INHIBITORS GUIDELINE 1653 of three cases of high-grade cancer after approxi- cers as clinically insignificant by histologic criteria, a mately 7 years of therapy. rate similar to contemporary series of men who un- Men also should be informed that no information dergo treatment.21 Many cancers prevented by finas- on the long-term effects of 5-ARIs exists beyond teride might never have caused harm, as suggested by approximately 7 years, and that whether or not the the fact that screening leads to substantial overdiag- reduction in prostate cancer incidence will translate nosis of nonlethal cancers. Overdiagnosis can increase into a reduction in prostate cancer mortality or substantially with a lowering of the PSA threshold for longer life expectancy remains unknown. prostatic biopsy or an increase in the number of sys- Physicians should inform men who are consider- tematic biopsies of the prostate. Overdiagnosis is ing a 5-ARI about the incidence of sexual adverse likely to decrease if ongoing randomized prostate can- effects. Such adverse effects as lowered libido asso- cer screening trials show a net harm from screening. ciated with a 5-ARI have been reported consistently, Therefore, the clinical importance of the prostate can- but they are also reversible. The benefits of a 5-ARI cers diagnosed in existing and ongoing chemopreven- in reducing BPH are also appreciable and unequiv- tion trials is difficult to interpret. The Panel attempted ocal. It has been suggested that the ideal candidate to focus on cancers that were most likely to be of for a 5-ARI regimen would be an individual who is clinical importance (for-cause cancers as described in “concerned about the development of prostate can- Methods). One of the most serious limitations in the cer, has a higher-than-average risk of the disease, current literature is the changes that occur in stan- has urinary symptoms that may be relieved by fin- dards for PSA thresholds, criteria for biopsy, and bi- asteride, and is not sexually active.”30 opsy methods. Continuing changes may alter all eval- In summary, it is recommended that the physi- uations of outcomes. cian: Although not specifically within the scope of this document, the Panel did review studies on cost effec- 1. inform the man who is considering a 5-ARI that these agents reduce the incidence of prostate can- tiveness. Two analyses31,32 have been published on the cer, and be sure to be clear that these agents do cost effectiveness of finasteride for prostate cancer pre- not reduce the risk of prostate cancer to zero; vention using the period prevalence observed in the 2. discuss the elevated rate of high-grade cancer PCPT and making a variety of unverifiable assump- observed in the PCPT and inform men of the tions about the impact of the diagnosed cancers on potential explanations; prostate cancer mortality and the tumor grade-specific 3. make it known to men that no information on the lethality of the cancers detected. The results of the long-term effects of 5-ARIs on prostate cancer cost-effectiveness analyses were highly dependent on incidence exists beyond approximately 7 years, assumptions regarding whether the observed increase and that whether or not a 5-ARI reduces prostate in high-grade tumors was real or artifactual, and on cancer mortality or increases life expectancy re- the cost of drug. As extensively discussed above, the mains unknown; first assumption cannot be tested. Therefore, the 4. inform men of possible but reversible sexual ad- Panel concluded that any assessment of cost effective- verse effects; and ness at this point is unreliable and impossible to in- 5. inform men of the likely improvement in lower corporate into the decision of whether or not to take urinary tract symptoms. 5-ARIs for lowering the risk of prostate cancer. LIMITATIONS OF THE LITERATURE SUMMARY OF DESIRED OUTCOMES Despite high-quality evidence from randomized trials, AND INTERPRETIVE SUMMARY the data have limitations. Only one trial reported to For the man who wishes periodic monitoring (oppor- date (PCPT) was specifically designed to measure the tunistic or organized screening), 5-ARI therapy dur- effect of a 5-ARI on the incidence of prostate cancer; it ing a 7-year period reduces the period prevalence of was not designed with sufficient power to assess the for-cause cancer diagnoses by approximately 25% effect of 5-ARIs on the risk of prostate cancer death. To (relative risk reduction) for an absolute risk reduc- develop a complete assessment of the benefit of tion of about 1.4%. Although the majority of the 5-ARIs, one would need to know the proportion of Panel judged that the observed higher incidence of cancers finasteride prevents that are truly clinically high-grade (Gleason score 8 to 10) cancer in the meaningful. The current literature cannot provide an finasteride group is likely due to confounding fac- estimate of this proportion; in particular, data are tors, the increased incidence of high-grade cancer as lacking on clinically meaningful cancers in the age a result of induction by the drug cannot be excluded group under consideration (men older than 50 years). with certainty. Additional benefits accruing from the A recent analysis of PCPT characterized 34% of can- drug are reduction of the risk of urinary retention and
  • 13. 1654 5 -REDUCTASE INHIBITORS GUIDELINE need for surgical intervention. Harms include sexual ter C. Albertsen, Joseph P. Costantino, Jonathan I. adverse effects, which usually diminish with time. Epstein, Timothy J. Wilt, Janet Wittes, Robin Zon, Paul Schellhammer Final approval of manuscript: Barnett S. Kramer, AUTHOR CONTRIBUTIONS Stewart Justman, Peter C. Albertsen, William J. Conception and design: Barnett S. Kramer, Timothy Blot, H. Ballentine Carter, Joseph P. Costantino, J. Wilt, Robin Zon, Paul Schellhammer Jonathan I. Epstein, Paul A. Godley, Russell P. Har- Administrative support: Karen L. Hagerty, Mark ris, Timothy J. Wilt, Janet Wittes, Robin Zon, Paul R. Somerfield Schellhammer Collection and assembly of data: Barnett S. Kramer, Karen L. Hagerty, Mark R. Somerfield, Timothy J. Wilt, Paul Schellhammer ACKNOWLEDGMENTS Data analysis and interpretation: Barnett S. The Expert Panel thanks Erik Busby, MD, William Kramer, Karen L. Hagerty, Stewart Justman, Peter Dahut, MD, Bernard Levin, MD, Ethan Basch, MD, C. Albertsen, H. Ballentine Carter, Joseph P. J. Leonard Lichtenfeld, MD, Dean F. Bajorin, MD, Costantino, Jonathan I. Epstein, Paul A. Godley, Bruce J. Roth, MD, the ASCO Health Services Com- Timothy J. Wilt, Janet Wittes, Paul Schellhammer mittee and Board of Directors and the AUA Practice Manuscript writing: Barnett S. Kramer, Karen L. Guidelines Committee, Board of Directors and staff, Hagerty, Stewart Justman, Mark R. Somerfield, Pe- Edie Budd, and Heddy Hubbard, PhD. TABLE A1 5- -Reductase Inhibitors Panel Members Panel Member Institution Barnett Kramer, MD, Co-Chair National Institutes of Health Paul Schellhammer, MD, Co-Chair Eastern Virginia Medical School Stewart Justman, PhD, Patient Representative University of Montana Liberal Studies Peter C. Albertsen, MD University of Connecticut Health Center William J. Blot, PhD International Epidemiology Institute, Vanderbilt-Ingram Cancer Center H. Ballentine Carter, MD Johns Hopkins University Joseph P. Costantino, PhD National Surgical Adjuvant Breast and Bowel Project Jonathan I. Epstein, MD Johns Hopkins University Paul A.Godley, MD, PhD University of North Carolina at Chapel Hill Russell P. Harris, MD, MPH University of North Carolina at Chapel Hill Timothy J. Wilt, MD, MPH Minneapolis VA Center for Chronic Disease Outcomes Research Janet Wittes, PhD Statistics Collaborative Robin Zon, MD Michiana Hematology Oncology TABLE A2 Characteristics for 5-ARI Studies No. of Randomly Treatment Study (references) and Assigned Duration Interventions (dose/d) Patients (years) Baseline Demographic Characteristics Long-term trials ( 2 years) PCPT5 7( 90 days) American men enrolled onto a prostate cancer prevention trial Finasteride, 5 mg 9,423 Age, 45–64 years, 62%; 65 years, 38% Placebo 9,459 Race/ethnicity: white, 92%; black, 3.8%; Hispanic, 2.6%; other, 1.5% PSA (ng/mL), 3: 100% Family history of PCa (first-degree relative): 15.4% Mean baseline AUA/IPSS score: 6.7 (SD, 4.8) MTOPS10,33 4.5 American men, mean age 62.6 (SD, 7.3), with LUTS secondary to BPH Finasteride, 5 mg 768 Race/ethnicity: white, 82.3%; black, 8.9%; Hispanic, 7.3%; other, 1.5% Doxazosin, 4–8 mg 756 Mean PSA (ng/mL): 2.4 (SD, 2.1) Combination finasteride and doxazsoin 786 Mean prostate volume (mL): 36.3 (SD, 20.1) Placebo 737 Mean baseline AUA/IPSS score: 16.9 (SD, 5.9) PLESS9,34–37 4.0 American men, mean age 64 years (SD, 6.4), with LUTS secondary BPH Finasteride, 5 mg 1,524 Race: white 95.5% Placebo 1,516 Mean PSA (ng/mL): 2.8 (SD, 2.1). Mean baseline AUA/IPSS score: 15 (SD, 5.7). History of sexual dysfunction: 46% of men in each group at screening (appendix continued)
  • 14. 5 -REDUCTASE INHIBITORS GUIDELINE 1655 TABLE A2 (continued) No. of Randomly Treatment Study (references) and Assigned Duration Interventions (dose/d) Patients (years) Baseline Demographic Characteristics Moderate-term trials (1–2 years) ARIA/ARIB 3001, 3002, 30038,38–40 2.0 Multinational men, mean age 66.3 years, with LUTS secondary BPH (all participants had IPSS 12) Dutasteride, 0.5 mg 2,167 Race/ethnicity: white, 92%; black, 4%; Hispanic, 7.3%; Asian, 1%; other, 1.5% Placebo 2,158 Mean PSA (ng/mL): 4.0 (SD, 2.1) Mean prostate volume (cm3): 54.5 Mean baseline AUA/IPSS score: 17.05 PROSPECT41 2.0 Canadian men in good health, mean age, 63.3 years (range, 46 to 80 years) with LUTS secondary to BPH Finasteride, 5 mg 310 Race: NR Placebo 303 Mean PSA (ng/mL): NR Mean baseline AUA/IPSS score: 16.2 PREDICT24 1.0 European men, mean age, 64 years (range, 50 to 80 years), with LUTS secondary to BPH (all participants had IPSS 12) Finasteride, 5 mg 264 Race: NR Doxazosin, 4–8 mg 275 Mean PSA (ng/mL): 2.6 Combination finasteride and doxazsoin 286 Mean prostate volume (g): 36 Placebo 270 Mean baseline AUA/IPSS score: 17.2 VA Coop (Johnson, 2003; a subset of 1.0 American men, mean age 65 years, with symptomatic BPH subjects from Lepor 1996)25,42 Finasteride, 5 mg 252 Race: white 80% Terazosin, 10 mg 262 Race/ethnicity (from Lepor): white, 87%; black, 11%; Asian, 1%; Native American, 0.5% Combination finasteride and terazosin 272 Mean PSA (from Lepor; ng/mL): 2.3 Placebo 254 Mean prostate volume (g): 37.6 Mean baseline AUA/IPSS score: 16.1 Foley, 200022 1.0 British men, mean age, 77.5 years (range, 55 to 89 years), with hematuria associated with BPH Finasteride, 5 mg 29 Race: NR Watchful waiting 28 Mean PSA (ng/mL): NR Mean baseline AUA/IPSS score: NR Cote, 199843 1.0 American men age 50 years (mean, 68 years) with elevated PSA ( 4.0 ng/mL); study objective was to examine effect of finasteride on prostate cellular proliferation and high-grade PIN Observation (watchful waiting) 29 Race: NR Finasteride, 5 mg 29 Mean PSA (ng/mL): 9.8 Mean baseline AUA/IPSS score: NR Pre-existing high-grade PIN: observation, 5 men; Finasteride, 8 men FSG44–48 American and international men; mean age, 64.9 years (range, 40 to 83 years) with BPH Finasteride, 1 mg 547 Race/ethnicity: white, 95.8%; black, 1.6%; other, 2.6%. Finasteride, 5 mg 543 Mean PSA (ng/mL): 4.7 Placebo 555 Mean prostate volume (cm3): 55.0 Mean baseline AUA/IPSS score: NR Short-term trials (1 year) ARIA 200149 0.5 American and Canadian men age 50 years (mean, 62.6 to 65.5 years across groups), with LUTS secondary to BPH; study objective was to examine effect of dutasteride on serum dihydrotestosterone levels Dutasteride, 0.01, 0.05, 0.5, 2.5, and 285 Race: NR 5 mg Finasteride, 5 mg 55 Mean PSA (ng/mL): NR Placebo 59 Mean baseline AUA/IPSS score: NR MICTUS50 0.5 Italian men, mean age, 63 years (SD, 7.1 years), with LUTS secondary to BPH (all participants had IPSS 13) Finasteride, 5 mg 204 Race: NR Tamsulosin, 0.4 mg 199 Mean PSA (ng/mL): NR Mean baseline AUA/IPSS score: NR Lee, 200251 Korean men, mean age, 64.7 years, with LUTS secondary to BPH (all participants had Korean IPSS 8) Finasteride, 5 mg 102 Race: Asian, 100% Tamsulosin, 0.2 mg 103 Mean PSA (ng/mL): 2.0 Mean prostate volume (cm3): 29.8 Mean baseline AUA/IPSS score: 19.5 Abbreviations: 5-ARI, 5- -reductase inhibitor; PCPT, Prostate Cancer Prevention Trial; PSA, prostate-specific antigen; PCa, prostate cancer; AUA/IPSS, American Urological Association/International Prostate Symptom Score; SD, standard deviation; NR, not reported; MTOPS, Medical Therapy of Prostatic Symptoms; LUTS, lower urinary tract symptoms; BPH, benign prostatic hyperplasia; PLESS, Proscar Long-Term Efficacy and Safety Study; PREDICT, Prospective European Doxazosin and Combination Therapy; PIN, prostatic intraepithelial neoplasia; FSG, Finasteride Study Group; MICTUS, Multicentre Investigation to Characterise the Effect of Tamsulosin on Urinary Symptoms.
  • 15. 1656 5 -REDUCTASE INHIBITORS GUIDELINE TABLE A3 Period Prevalence of Prostate Cancer According to Subgroup 5- -Reductase Inhibitor Placebo No./Total No. No./Total No. Relative Subgroup/Reference of Patients % of Patients % Risk 95% CI PSA at study entry: 0.0 to 4.0 ng/mL PCPT5 803/9,423 8.5 1,147/9,456 12.1 0.70 0.64 to 0.77 PLESS36 28/1,149 2.4 32/1,154 2.8 0.88 0.53 to 1.45 Total 831/10,572 7.9 1,179/10,610 11.1 0.71 0.65 to 0.77 PSA at study entry: 4.0 ng/mL Cote43 8/27 29.6 1/25 4.0 7.41 1.00 to 55.09 PLESS36 44/374 11.8 45/357 12.6 0.93 0.63 to 1.38 Total 52/401 13.0 46/382 12.0 2.08 0.28 to 15.43 Gleason score 7 PCPT5 190/9,423 2.0 184/9,459 1.9 1.04 0.85 to 1.27 PLESS (estimated from graph)36 11/1,524 0.72 12/1,516 0.79 0.91 0.40 to 2.06 Total 201/10,947 1.8 196/10,975 1.9 1.03 0.85 to 1.25 Gleason score 7: PCPT5 PCa overall/number randomized 190/9,423 2.0 184/9,459 1.9 1.04 0.85 to 1.27 PCa overall/included in analysis 190/4,368 4.3 184/4,692 3.9 1.11 0.91 to 1.35 PCa detected for cause/number randomized 118/9,423 12.5 103/9,459 10.9 1.15 0.88 to 1.50 PCa detected for cause/biopsy performed for cause 118/1,639 7.2 103/1,934 5.3 1.35 1.05 to 1.75 Gleason scores 8 to 10 PCPT5 90/9,423 0.96 53/9,459 0.56 1.70 1.22 to 2.39 PLESS (estimated from graph)36 1/1,524 0.07 7/1,516 0.46 0.14 0.02 to 1.15 Gleason scores 8 to 10: PCPT5 PCa overall/No. randomly assigned 90/9,423 0.96 53/9,459 0.56 1.70 1.22 to 2.39 PCa overall/No. included in analysis 90/4,368 2.1 53/4,692 1.1 1.82 1.30 to 2.55 PCa detected for cause/No. randomly assigned 70/9,423 0.74 45/9,459 0.48 1.56 1.07 to 2.27 PCa detected for cause/No. with biopsy performed 70/1,639 4.3 45/1,934 2.3 1.84 1.27 to 2.65 for cause Age, years: PCPT5 55 to 59 205/2,954 6.9 309/2,954 10.5 0.66 0.56 to 0.79 60 to 64 254/2,970 8.6 357/2,825 12.6 0.68 0.58 to 0.79 65 344/3,498 9.8 481/3,677 13.1 0.75 0.66 to 0.86 Race/ethnicity: PCPT5 Non-Hispanic white 739/8,667 8.5 1067/8,713 12.2 0.70 0.64 to 0.76 African-American 41/356 11.5 50/353 14.2 0.81 0.55 to 1.20 Hispanic 19/262 7.3 23/237 9.7 0.75 0.42 to 1.34 Family history of PCa in first-degree relative: PCPT5 Yes 176/1,458 12.1 241/1,455 16.6 0.73 0.61 to 0.87 No 627/7,965 7.9 906/8,002 11.3 0.70 0.63 to 0.77 Abbreviations: PSA, prostate-specific antigen; PCPT, Prostate Cancer Prevention Trial; PLESS, Proscar Long-Term Efficacy and Safety Study; PCa, prostate cancer. REFERENCES 1. Chlebowski RT, Sayre J, Frank-Stromborg M, et al: status of the National Surgical Adjuvant Breast and 8. Roehrborn CG, Boyle P, Nickel JC, et al: Efficacy and Current attitudes and practice of American Society Bowel Project P-1 study. J Natl Cancer Inst 2005; safety of a dual inhibitor of 5-alpha-reductase types of Clinical Oncology-member clinical oncologists re- 97: 1652. 1 and 2 (dutasteride) in men with benign prostatic garding cancer prevention and control. J Clin Oncol hyperplasia. Urology 2002; 60: 434. 1992; 10: 164. 5. Thompson IM, Goodman PJ, Tangen CM, et al: The influence of finasteride on the development of pros- 2. Ganz PA, Kwan L, Somerfield MR, et al: The role of 9. Kaplan S, Garvin D, Gilhooly P, et al: Impact of tate cancer. N Engl J Med 2003; 349: 215. prevention in oncology practice: Results from a baseline symptom severity on future risk of benign 2004 survey of American Society of Clinical Oncol- prostatic hyperplasia-related outcomes and long- 6. Vogel VG, Costantino JP, Wickerham DL, et al: ogy members. J Clin Oncol 2006; 24: 2948. term response to finasteride: The Pless Study Effects of tamoxifen vs raloxifene on the risk of Group. Urology 2000; 56: 610. 3. Fisher B, Costantino JP, Wickerham DL, et al: Ta- developing invasive breast cancer and other disease moxifen for prevention of breast cancer: Report of outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006; 295: 2727. 10. McConnell JD, Roehrborn CG, Bautista OM, et al: the National Surgical Adjuvant Breast and Bowel The long-term effect of doxazosin, finasteride, and Project P-1 Study. J Natl Cancer Inst 1998; 90: 1371. 7. AUA guideline on management of benign prostatic combination therapy on the clinical progression of 4. Fisher B, Costantino JP, Wickerham DL, et al: Ta- hyperplasia: (2003). Chapter 1: Diagnosis and treat- benign prostatic hyperplasia. N Engl J Med 2003; moxifen for the prevention of breast cancer: Current ment recommendations. J Urol 2003; 170: 530. 349: 2387.
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